Brain gene expression in systemic hypothyroidism and in mouse models of MCT8 deficiency: The Mct8-Oatp1c1-Dio2 triad.

The monocarboxylate transporter 8 (Mct8) protein is a primary T4 and T3 (TH) transporter. Mutations of the MCT8-encoding, SLC16A2 gene alters thyroid function and thyroid hormone metabolism, and severely impairs neurodevelopment (Allan-Herndon-Dudley syndrome, AHDS). Mct8-deficient mice manifest thyroid alterations but lack neurological signs. It is thought that Mct8 deficiency in mice is compensated by T4 transport through the Slco1c1-encoded organic anion transporter polypeptide 1c1 (Oatp1c1). This allows local brain generation of sufficient T3 by the Dio2-encoded type 2 deiodinase (D2). The Slc16a2/Slco1c1 (MO) and Slc16a2/Dio2 (MD) double knock out mice lacking T4 and T3 transport, or T3 transport and T4 deiodination, would be more approriate models of AHDS. The goal of this work was to compare the cerebral hypothyroidism of systemic hypothyroidism (SH) caused by thyroid gland blockade with that present in the double KOs. We performed RNA sequencing using RNA from the cerebral cortex and striatum from SH mice and the double KO on postnatal days 21-23. Systemic hypothyroidism was induced in WT male mice of the C57BL/6J strain by administration of 0.02% 1-methyl-2-mercapto-imidazol plus 1% KClO4 in the drinking water ad libitum to the pregnant and lactating dams. Antithyroid treatment started on E9 and continued until P21.